Heterocycle carboxamides as antiviral agents

ABSTRACT

The present invention provides a compound of formula I  
                 
 
     which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the following provisionalapplication: U.S. Ser. No: 60/218116, filed Jul. 13, 2000, under 35 USC119(e)(i).

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention provides heterocycle carboxamidederivatives. These compounds are useful as antiviral agents, inparticular, as agents against viruses of the herpes family.

[0004] 2. Technology Description

[0005] The herpesviruses comprise a large family of double stranded DNAviruses. They are also a source of the most common viral illnesses inman. Eight of the herpes viruses, herpes simplex virus types 1 and 2(HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus(HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8(HHV-6, HHV-7, and HHV-8), have been shown to infect humans.

[0006] HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals,respectively. They also occasionally cause infections of the eye andencephalitis. HCMV causes birth defects in infants and a variety ofdiseases in immunocompromised patients such as retinitis, pneumonia, andgastrointestinal disease. VZV is the causative agent of chicken pox andshingles. EBV causes infectious mononucleosis. It can also causelymphomas in immunocompromised patients and has been associated withBurkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease.HHV-6 is the causative agent of roseola and may be associated withmultiple sclerosis and chronic fatigue syndrome. HHV-7 diseaseassociation is unclear, but it may be involved in some cases of roseola.HHV-8 has been associated with Karposi's sarcoma, body cavity basedlymphomas, and multiple myeloma.

[0007] U.S. Pat. Nos. 5,753,666 and 5,891,878 and WO 97/04775 disclosespecific 1-alkyl-substituted-quinolone-3-carboxamides that are allegedto have therapeutic utility via inhibition of Phosphodiesterase IVesterase and/or Tumor Necrosis factor activity.

[0008] Commonly assigned WO 00/40561 discloses quinolinecarboxamides asantiviral agents.

[0009] Commonly assigned WO 00/40563 discloses specificquinolinecarboxamides as antiviral agents.

[0010] Commonly assigned WO 00/53610 discloses4-Oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides as antiviralagents.

[0011] Commonly assigned WO99/32450 discloses specific4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.

[0012] U.S. Pat. No. 5,945,431 discloses specific naphthyridineheterocyclic compounds having antiviral activity that are useful in thetherapy and prophylaxis of cytomegalovirus (CMV) infection in mammals.

[0013] WO99/10347 discloses specific substituted4-oxo-naphthyridine-3-carboxamides as brain receptor ligands havingpotential use in the treatment of central nervous system diseases and/ordisorders.

[0014] WO98/19673 discloses specific heterocyclic agents for thetreatment of diseases caused by viruses.

[0015] JP08301849 discloses specific heterocyclic agents useful astachykinin receptor antagonists. They are suggested for use in treatmentof the following diseases: inflammation, allergic diseases, CNSdisorders, digestive system disorders, urinary tract disorders,cardiovascular diseases immunopathy. The reference suggests that theinventive compounds can be used to treat herpes, but classifies herpesas either an inflammation or allergic reaction disease. The referencedoes not suggest that the compounds can be used to treat infectiousdiseases.

[0016] JP07033729 discloses specificN-cyano-N′-substituted-arylcarboxyimidamide compounds exhibiting K+channel opening effects and having hypotensive action and coronaryvasodilating action.

[0017] WO 00/40562 discloses novel 2-oxoquinolines as selectiveperipheral cannabinoid receptor modulators).

[0018] WO 97/34894 dosloses Naphthyridine derivatives and theiranalogues inhibiting cytomegalovirus.

[0019] Despite the above teachings, there still exists a need in the artfor novel compounds that demonstrate desirable antiviral activity.

BRIEF SUMMARY OF THE INVENTION

[0020] In accordance with the present invention, novel compounds whichdemonstrate antiviral activity are provided. More specifically, thecompounds are specific heterocycle carboxamide derivatives which areuseful as antiviral agents, particularly against herpes viruses.

[0021] Even more specifically, the present invention provides a compoundof formula I,

[0022] wherein,

[0023] X is Cl, Br, F, CN or NO₂;

[0024] G is

[0025] (a) C₃₋₇alkyl which is partially unsaturated and is substitutedby hydroxy, or

[0026] (b) C₁₋₇alkyl substituted by NR¹R² or 4-tetrahydropyran;

[0027] R¹ is C₂₋₇alkyl substituted by hydroxy, C₁₋₄alkoxy, aryl, orheteroaryl;

[0028] R² is hydrogen or C₁₋₇alkyl;

[0029] or R¹ and R² together with the nitrogen to which they areattached form morpholine which may be optionally substituted by aryl orC₁₋₇alkyl;

[0030] W is

[0031] B is CR⁵ or nitrogen;

[0032] C is CR⁶ or nitrogen;

[0033] with the provisos that B and C cannot be both nitrogen;

[0034] R⁴ is H, halogen, or C₁₋₄alkyl optionally substituted by one tothree halogens;

[0035] R⁵ is

[0036] (a) H,

[0037] (b) halo,

[0038] (c) OR¹²,

[0039] (d) SR¹²,

[0040] (e) C₁₋₇alkyl which may be partially unsaturated and optionallysubstituted by one or more substituents selected from OR¹², SR¹²,NR¹⁰R¹¹, or halo,

[0041] (f) C₃₋₈cycloalkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected fromhalogen, OR¹² SR¹²,or NR¹⁰R¹¹,

[0042] (g) (C═O)R⁹,

[0043] (h) S(O)_(m)R⁹,

[0044] (i) (C═O)OR²,

[0045] (j) NHSO₂R⁹,

[0046] (k) nitro, or

[0047] (l) cyano;

[0048] R⁶ is

[0049] (a) H,

[0050] (b) halo,

[0051] (c) aryl,

[0052] (d) het, or

[0053] (e) R7;

[0054] R⁷ is

[0055] (a) OR¹²,

[0056] (b) SR¹²,

[0057] (c) C₁₋₇alkyl which may be partially unsaturated and optionallysubstituted by one or more substituents selected from OR¹², SR¹²,NR¹⁰R¹¹, aryl, halo,

[0058] C ₃₋₈cycloalkyl optionally substituted by OR¹², or het attachedthrough a carbon atom,

[0059] (d) NR¹⁰R¹¹,

[0060] (e) C₃₋₈cycloalkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected fromhalogen, OR¹², SR¹²,or NR¹⁰R¹¹,

[0061] (f) (C═O)R⁹,

[0062] (g) S(O)_(m)R⁹,

[0063] (h) (C═O)OR²,

[0064] (i) NHSO₂R⁹,

[0065] (j) nitro, or

[0066] (k) cyano;

[0067] R⁸ is

[0068] (a) H,

[0069] (b) C₁₋₇alkyl which may be partially unsaturated and optionallysubstituted by one or more substituents selected from OR¹², SR¹²,NR¹⁰R¹¹, or halo,

[0070] (c) OR¹², or

[0071] (d) SR¹²;

[0072] R⁹ is

[0073] (a) C₁₋₇alkyl,

[0074] (b) NR¹⁰R¹¹,

[0075] (c) aryl, or

[0076] (d) het, wherein said het is bound through a carbon atom;

[0077] R¹⁰ and R¹¹ are independently

[0078] (a) H,

[0079] (b) aryl,

[0080] (c) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected fromCONR²R², CO₂R², het, aryl, cyano, or halo,

[0081] (d) C₂₋₇alkyl which may be partially unsaturated and issubstituted by one or more substituents selected from NR²R², OR², orSR²,

[0082] (e) C₃₋₈cycloalkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected fromhalogen, OR², SR², or NR²R², or

[0083] (f) R¹⁰ and R¹¹ together with the nitrogen to which they areattached form a het;

[0084] R¹²

[0085] is (a) H,

[0086] (b) aryl,

[0087] (c) het

[0088] (d) C₁₋₇alkyl optionally substituted by aryl, het, or halogen,

[0089] (e) C₂₋₇alkyl substituted by OR², SR², or NR²R², or

[0090] (f) C₃₋₈cycloalkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected fromhalogen, OR², SR², or NR²R²;

[0091] each m is independently 1 or 2;

[0092] aryl is a phenyl radical or an ortho-fused bicyclic carbocyclicradical wherein at least one ring is aromatic, and aryl maybe optionallysubstituted with one or more substituents selected from halo, OH, cyano,NR²R², CO₂R², CF₃, C₁₋₆alkoxy, and C₁₋₆ alkyl which maybe furthersubstituted by one to three SR², NR²R², OR², or CO₂R² groups;

[0093] het is a four- (4), five- (5), six- (6), or seven- (7) memberedsaturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatomsselected from oxygen, sulfur, or nitrogen, which is optionally fused toa benzene ring, or any bicyclic heterocycle group, and het may beoptionally substituted with one or more substituents selected from halo,OH, cyano, phenyl, CO₂R², CF₃, C₁₋₆alkoxy, oxo, oxime, and C₁₋₆ alkylwhich may be further substituted by one to three SR², NR²R², OR², orCO₂R² groups;

[0094] halo or halogen is F, Cl, Br, I;

[0095] 1 represents the point of attachment between W and G;

[0096] 2 represents the point of attachment between W and the carbonylgroup of Formula (I);

[0097] and a pharmaceutically acceptable salt thereof.

[0098] In particularly preferred embodiments, X is Cl and G is4-morpholinylmethyl.

[0099] Another embodiment of the present invention provides apharmaceutical composition comprising a compound of formula (I) asdefined above, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier. In preferred embodiments, thecomposition preferably comprises a therapeutically effective amount ofthe compound or salt.

[0100] Still another embodiment of the present invention provides amethod for treating a disease or condition in a mammal caused by a viralinfection, particularly a herpes viral infection, comprisingadministering to the mammal a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.For this embodiment, in addition to the compounds encompassed by formula(I), G can also represent C₁₋₇alkyl which is fully saturated and issubstituted by hydroxy.

[0101] A further embodiment of the present invention comprises the useof a compound of formula (I) or a pharmaceutically acceptable saltthereof to prepare a medicament for treating or preventing diseases ordisorders caused by a viral infection, and particularly a herpes viralinfection.

[0102] A final embodiment of the present invention comprises a methodfor inhibiting a viral DNA polymerase, comprising contacting (in vitroor in vivo) the polymerase with an effective inhibitory amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

[0103] An object of the present invention is to provide novel compoundshaving biological activity.

[0104] A further object of the present invention is to provide novelpharmaceutical compositions.

[0105] Still another object of the present invention is to provide amethod for treating a disease or condition in a mammal caused by a viralinfection, particularly a herpes virus infection.

[0106] Another object of the present invention is to provide a methodfor inhibiting a viral DNA polymerase.

[0107] These, and other objects, will readily be apparent to thoseskilled in the art as reference is made to the detailed description ofthe preferred embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0108] In describing the preferred embodiment, certain terminology willbe utilized for the sake of clarity. Such terminology is intended toencompass the recited embodiment, as well as all technical equivalentswhich operate in a similar manner for a similar purpose to achieve asimilar result.

[0109] 1. Terminology Definitions

[0110] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl denotes both straight andbranched groups; but reference to an individual radical such as “propyl”embraces only the straight chain radical, a branched chain isomer suchas “isopropyl” being specifically referred to. When alkyl can bepartially unsaturated, the alkyl chain may comprise one or more (e.g.,1, 2, 3, or 4) double or triple bonds in the chain.

[0111] Aryl denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical wherein at least one ring is aromatic. Het is afour- (4), five- (5), six- (6), or seven- (7) membered saturated orunsaturated ring containing 1, 2 or 3 heteroatoms selected from thegroup consisting of non-peroxide oxygen, sulfur, and nitrogen, which isoptionally fused to a benzene ring, or any bicyclic heterocyclic group.Het includes “heteroaryl”, which encompasses a radical attached via aring carbon of a monocyclic aromatic ring containing five or six ringatoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selectedfrom the group consisting of non-peroxide oxygen, sulfur, and N(X)wherein X is absent or is H, O, C₁₋₄alkyl, phenyl or benzyl.

[0112] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase) andhow to determine antiviral activity using the standard tests describedherein, or using other similar tests which are well known in the art.

[0113] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating a lower and upper numberof carbon atoms in the moiety, i.e., the prefix C_(i-j) indicates amoiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, C₁₋₇alkyl refers to alkyl of one to seven carbonatoms, inclusive.

[0114] The compounds of the present invention are generally namedaccording to the IUPAC or CAS nomenclature system. Abbreviations whichare well known to one of ordinary skill in the art may be used (e.g.“Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hoursand “rt” for room temperature).

[0115] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents. The compounds of the invention includecompounds of formula (I) having any combination of the values, specificvalues, more specific values, and preferred values described herein.

[0116] Mammal denotes human and animals, specifically including foodanimals and companion animals.

[0117] 2. The Invention

[0118] The present invention comprises compounds of formula (I) asdefined above, and their pharmaceutically acceptable salts.

[0119] For the compounds of formula (I), alkyl can be methyl, ethyl,propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl,heptyl, etc.; C₃₋₈cycloalkyl can be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; alkoxy can bemethoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy,pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy, or heptyloxy; het can beazetidinyl, 3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino,morpholino, thiomorpholino, or heteroaryl; and heteroaryl can be furyl,imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl,isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (orits N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

[0120] When alkyl is partially unsaturated, it can be vinyl, allyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or5-hexynyl.

[0121] Specific examples of W include,

[0122] Particularly preferred compounds are those where X is Cl and G is4-morpholinylmethyl.

[0123] Examples of the present invention include, but are not limited tothe following:

[0124] N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-isoquinolinecarboxamide;

[0125]N-(4-chlorobenzyl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-ylmethyl)-6-isoquinoline-carboxamide;

[0126] N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-6-isoquinolinecarboxarnide;

[0127]N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-quinolinecarboxamide;

[0128] or a pharmaceutically acceptable salt thereof.

[0129] Representative examples of the synthesis of compounds fallingwithin the scope of formula W as follows.

[0130] The following Charts A-D describe the preparation of thecompounds of the present invention. All of the starting materials areprepared by procedures described in these charts or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the final compounds of the present inventionare prepared by procedures described in these charts or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the variables used in the charts are asdefined below or as in the claims.

[0131] W2.1. 5-Hydroxy-6-isoquinolinecarboxamides. Preparation ofspecific examples of heterocycle W2.1 follows an established literatureprecedent set forth in Tetrahedron 1973, 29, 857. and elaborated on inCharts A and B below. Benzaldehyde A.1 is condensed with2-amino-3,3-dimethoxy-1-propanol (Carbohydrate Res. 1969, 10, 35-48.) toafford the corresponding imine A.2. Cyclization of A.2 by heating theimine in a mixture of polyphoric acid (PPA) provides the isoquinolineA.3. Compound A.3 is heated in the presence of a benzylamine (e.g.4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) toprovide amides of the general formula A.4. Oxidation of the benzylicalcohol with manganese(IV)oxide or other suitable oxidizing agentaffords a corresponding aldehyde of the formula A.5 which undergoesreductive amination with an amine (e.g. morpholine), acetic acid, andsodium triacetoxyborohydride to provide a compound such as A.6.

[0132] Alternatively, to prepare compounds of structure W2.1 whereG=4-tetrahydro-pyranylmethyl, intermediate A.5 is protected as amethoxymethylether or other suitable phenol protecting group (Green, T.W; Wuts, P. G. M. Protective Groups in Organic Synthesis. Wiley, 1999)to provide B.1, Chart B. Wittig olefination between B.1 and4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.;Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodiumhexamethyl-disilazide as base provides the olefin B.2. Hydrogenation ofB.2 catalyzed by palladium on carbon provides B.3 by which deprotectionof the phenol protecting group affords B.4. Similarly, to preparecompounds of structure W2. 1 where G=3-hydroxypropyl or3-hydroxy-l-propynyl, intermediate B.1 is reacted withdimethoxy-diazomethylphosoniumoxide in the presence of a suitable basesuch as potassium tert-butoxide (Tetrahedron Lett. 1992, 33, 3715) toafford the corresponding acetylene of the formula C.1, Chart C. Additionof the lithium anion of acetylene C.1 prepared with lithiumdiisopropylamide or other suitable base to formaldehyde or aformaldehyde equivalent provides C.2 which following deprotection of thephenol affords derivatives of the formula C.3. Saturation of the alkyneby hydrogenation catalyzed by palladium on carbon in alcoholic solventsaffords alkyl derivatives of formula C.4

[0133] W2.2. 5-Hydroxy-6-quinolinecarboxamides. The preparation ofspecific examples of heterocycle W2.2. where G is 4-morpholinylmethyl isdescribed in Chart D. Benzylic bromination of quinoline D.1 (J. M.Muchowski J. Org. Chem. 1991, 56, 7288-7291.) affords alkylbromide D.2.Displacement of D.2 with morpholine provides quinoline D.3. Metalationof D.3 with n-butyllithium at low temperature and trapping of theresulting anion with carbon dioxide provides carboxylic acid D.4. Theresulting carboxylic acid D.4 is then coupled with a benzylamine (e.g.4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine)mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acidactivating agent) to provide amides of the general formula D.5.Deprotection of the methylether by reaction with boron tribromideprovides hydroxyquinolines of the formula D.6.

[0134] The inventive compounds may be used in their native form or assalts. In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,etoglutarate, and glycerophosphate. Suitable inorganic salts may also beformed, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

[0135] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

[0136] Compounds of the present invention can conveniently beadministered in a pharmaceutical composition containing the compound incombination with a suitable excipient, the composition being useful incombating viral infections. Pharmaceutical compositions containing acompound appropriate for antiviral use are prepared by methods andcontain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed.,1975). The compounds and compositions of the present invention can beadministered parenterally (for example, by intravenous, intraperitonealor intramuscular injection), topically (including but not limited tosurface treatment, transdermal application, and nasal application),intravaginally, orally, or rectally, depending on whether thepreparation is used to treat internal or external viral infections.

[0137] For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0138] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices such as the osmotic release type devices developed by theAlza Corporation under the OROS trademark.

[0139] The compounds or compositions can also be administeredintravenously or intraperitoneally by infusion or injection. Solutionsof the active compound or its salts can be prepared in water, optionallymixed with a nontoxic surfactant. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, triacetin, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

[0140] Pharmaceutical dosage forms suitable for injection or infusioncan include sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0141] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0142] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0143] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers. Thickeners suchas synthetic polymers, fatty acids, fatty acid salts and esters, fattyalcohols, modified celluloses or modified mineral materials can also beemployed with liquid carriers to form spreadable pastes, gels,ointments, soaps, and the like, for application directly to the skin ofthe user.

[0144] Examples of useful dermatological compositions which can be usedto deliver the compounds of formula I to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

[0145] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0146] The compound is conveniently administered in unit dosage form;for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

[0147] For internal infections, the compositions can be administeredorally or parenterally at dose levels, calculated as the free base, ofabout 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal bodyweight, and can be used in man in a unit dosage form, administered oneto four times daily in the amount of 1 to 1000 mg per unit dose.

[0148] For parenteral administration or for administration as drops, asfor eye infections, the compounds are presented in aqueous solution in aconcentration of from about 0.1 to about 10%, more preferably about 0.1to about 7%. The solution may contain other ingredients, such asemulsifiers, antioxidants or buffers.

[0149] Generally, the concentration of the compound(s) of formula I in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

[0150] The exact regimen for administration of the compounds andcompositions disclosed herein will necessarily be dependent upon theneeds of the individual subject being treated, the type of treatmentand, of course, the judgment of the attending practitioner. Thecompounds of the present invention can be administered to an animal inneed of treatment. In most instances, this will be a human being, butthe treatment of livestock and companion animals is also specificallycontemplated as falling within the scope of the instant invention.

[0151] The compounds of formula (I) and pharmaceutically acceptablesalts thereof are useful as antiviral agents. Thus, they are useful tocombat viral infections in animals, including man. The compounds aregenerally active against herpes viruses, and are particularly usefulagainst the varicella zoster virus, the Epstein-Barr Virus, the herpessimplex virus types 1 and 2 (HSV-1 and 2), the human herpes virus types6, 7 and 8 (HHV-6, 7, and 8) and the human cytomegalovirus (HCMV).

[0152] The invention will be further described by the followingnon-limiting examples.

Testing of Inventive Compounds

[0153] The antiviral activity of a compound of the invention can bedetermined using pharmacological models which are well known to the art,or using the test described below.

[0154] While many of the compounds of the present invention candemonstrate activity against the CMV polymerase, these compounds may beactive against the cytomegalovirus by this or other mechanisms ofaction. Thus, the description below of these compounds' activity againstthe CMV polymerase is not meant to limit the present invention to aspecific mechanism of action.

[0155] The HCMV polymerase assay is performed using a scintillationproximity assay (SPA) as described in several references, such as N. D.Cook, et al., Pharmaceutical Manufacturing International, pages 49-53(1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S.Pat. No. 4,568,649 (1986); which are incorporated by reference herein.Reactions are performed in 96-well plates. The assay is conducted in 100μl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 MM MgCl₂, 0.36mg/ml BSA, and 90 nM ³H-dTTP. Assays are run with and without CHAPS,(3-[(3-Cholamidopropyl)-dimethylammonio]-1 -propane-sulfonate) at afinal concentration of 2 mM. HCMV polymerase is diluted in enzymedilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH7.5), 100 μg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, whichis expressed in recombinant baculovirus-infected SF-9 cells and purifiedaccording to literature procedures, is added at 10% (or 10 μl) of thefinal reaction volume, i.e., 100 μl. Compounds are diluted in 50% DMSOand 10 μl are added to each well. Control wells contain an equivalentconcentration of DMSO. Unless noted otherwise, reactions are initiatedvia the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primerto reaction mixtures containing the enzyme, substrate, and compounds ofinterest. Plates are incubated in a 25° C. or 37° C. water bath andterminated via the addition of 40 μl/reaction of 0.5 M EDTA (pH 8) perwell. Reactions are terminated within the time-frame during whichsubstrate incorporation is linear and varied depending upon the enzymeand conditions used, i.e., 30 min. for HCMV polymerase. Ten μl ofstreptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are addedfollowing termination of the reaction. Plates are incubated 10 min. at37° C., then equilibrated to room temperature, and counted on a PackardTopcount. Linear regressions are performed and IC₅₀'s are calculatedusing computer software.

[0156] A modified version of the above HCMV polymerase assay isperformed as described above, but with the following changes: Compoundsare diluted in 100% DMSO until final dilution into assay buffer. In theprevious assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol(DTT) is added to the polymerase buffer. Also, a different lot of CMVpolymerase is used, which appears to be more active resulting in a morerapid polymerase reaction.

[0157] Having described the invention in detail and by reference to thepreferred embodiments thereof, it will be apparent that modificationsand variations are possible without departing from the scope of theappended claims.

What is claimed is:
 1. A compound of formula I,

wherein, X is Cl, Br, F, CN or NO₂; G is (a) C₃₋₇alkyl which ispartially unsaturated and is substituted by hydroxy, or (b) C₁₋₇alkylsubstituted by NR¹R² or 4-tetrahydropyran; R¹ is C₂₋₇alkyl substitutedby hydroxy, C₁₋₄alkoxy, aryl, or heteroaryl; R² is hydrogen orC₁₋₇alkyl; or R¹ and R² together with the nitrogen to which they areattached form morpholine which may be optionally substituted by aryl orC₁₋₇alkyl; W is

B is CR⁵ or nitrogen; C is CR⁶ or nitrogen; with the provisos that B andC cannot be both nitrogen; R⁴ is H, halogen, or C₁₋₄alkyl optionallysubstituted by one to three halogens; R⁵ is (a) H, (b) halo, (c) OR¹²,(d) SR¹², (e) C₁₋₇alkyl which may be partially unsaturated andoptionally substituted by one or more substituents selected from OR¹²,SR¹², NR¹⁰R¹¹, or halo, (f) C₃₋₈cycloalkyl which may be partiallyunsaturated and is optionally substituted by one or more substituentsselected from halogen, OR¹², SR¹²,or NR¹⁰R¹¹, (g) (C═O)R⁹, (h)S(O)_(m)R⁹, (i) (C═O)OR², (j) NHSO₂R⁹, (k) nitro, or (l) cyano; R⁶ is(a) H, (b) halo, (c) aryl, (f) het, or (g) R7; R⁷ is (a) OR¹², (b) SR¹²,(d) C₁₋₇alkyl which may be partially unsaturated and optionallysubstituted by one or more substituents selected from OR¹², SR¹²,NR¹⁰R¹¹, aryl, halo, C₃₋₈cycloalkyl optionally substituted by OR¹², orhet attached through a carbon atom, (d) NR¹⁰R¹¹, (e) C₃₋₈cycloalkylwhich may be partially unsaturated and is optionally substituted by oneor more substituents selected from halogen, OR¹², SR¹², or NR¹⁰R¹¹, (f)(C═O)R⁹, (g) S(O)_(m)R⁹, (h) (C═O)OR², (i) NHSO₂R⁹, (j) nitro, or (k)cyano; R⁸ is (a) H, (b) C₁₋₇alkyl which may be partially unsaturated andoptionally substituted by one or more substituents selected from OR¹²,SR¹², NR¹⁰R¹¹, or halo, (c) OR¹², or (d) SR¹²; R⁹ is (a) C₁₋₇alkyl, (b)NR¹⁰R¹¹, (c) aryl, or (d) het, wherein said het is bound through acarbon atom; R¹⁰ and R¹¹ are independently (a) H, (b) aryl, (c)C₁₋₇alkyl which may be partially unsaturated and is optionallysubstituted by one or more substituents selected from CONR²R², CO₂R²,het, aryl, cyano, or halo, (d) C₂₋₇alkyl which may be partiallyunsaturated and is substituted by one or more substituents selected fromNR²R², OR², or SR², (e) C₃₋₈cycloalkyl which may be partiallyunsaturated and is optionally substituted by one or more substituentsselected from halogen, OR², SR², or NR²R², or (f) R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached form a het; R¹² is (a) H,(b) aryl, (c) het (d) C₁₋₇alkyl optionally substituted by aryl, het, orhalogen, (e) C₂₋₇alkyl substituted by OR², SR², or NR²R², or (f)C₃₋₈cycloalkyl which may be partially unsaturated and is optionallysubstituted by one or more substituents selected from halogen, OR², SR²,or NR²R²; each m is independently 1 or 2; aryl is a phenyl radical or anortho-fused bicyclic carbocyclic radical wherein at least one ring isaromatic, and aryl maybe optionally substituted with one or moresubstituents selected from halo, OH, cyano, NR²R², CO₂R², CF₃,C₁₋₆alkoxy, and C₁₋₆ alkyl which maybe further substituted by one tothree SR², NR²R², OR², or CO₂R² groups; het is a four- (4), five- (5),six- (6), or seven- (7) membered saturated or unsaturated heterocyclicring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, ornitrogen, which is optionally fused to a benzene ring, or any bicyclicheterocycle group, and het may be optionally substituted with one ormore substituents selected from halo, OH, cyano, phenyl, CO₂R², CF₃,C₁₋₆alkoxy, oxo, oxime, and C₁₋₆ alkyl which may be further substitutedby one to three SR², NR²R², OR², or CO₂R² groups; halo or halogen is F,Cl, Br, I; 1 represents the point of attachment between W and G; 2represents the point of attachment between W and the carbonyl group ofFormula (I); and a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1 wherein W is of the formula W2.1.
 3. A compound ofclaim 1 wherein W is of the formula W2.2.
 4. The compound according toclaim 1, wherein X is Cl.
 5. The compound according to claim 1 wherein Gis 4-morpholinylmethyl.
 6. The compound according to claim 1 wherein Gis 3-hydroxy-1-propynyl.
 7. The compound according to claim 1 wherein Gis tetrahydro-2H-pyran-4-ylmethyl.
 8. The compound according to claim 1which isN-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-isoquinolinecarboxamide;N-(4-chlorobenzyl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-ylmethyl)-6-isoquinoline-carboxamide;N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy- 1-propynyl)-6-isoquinolinecarboxamide;N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-quinolinecarboxamide;or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 10. A method of treating or preventing a viralinfection, comprising administering to a mammal in need of suchtreatment, a compound of claim
 1. 11. The method according to claim 10wherein said viral infection is a herpes virus infection.
 12. The methodaccording to claim 10 wherein said mammal is a human.
 13. The methodaccording to claim 10 wherein said mammal is a food animal or companionanimal.
 14. The method according to claim 10 wherein the infection isherpes simplex virus type 1 or 2, human herpes virus type, 6, 7, or 8,varicella zoster virus, human cytomegalovirus, or Epstein-Barr virus.15. The method according to claim 10 wherein the infection is herpessimplex virus type 1 or 2, human herpes virus type 8, varicella zostervirus, human cytomegalovirus, or Epstein-Barr virus.
 16. The methodaccording to claim 10 wherein the amount administered is from about 0.1to about 300 mg/kg of body weight.
 17. The method according to claim 10wherein the amount administered is from about 1 to about 30 mg/kg ofbody weight.
 18. The method according to claim 10 wherein the compoundis administered parenterally, topically, intravaginally, orally, orrectally.
 19. A method for inhibiting a viral DNA polymerase, comprisingcontacting the polymerase with an effective inhibitory amount of acompound of the formula (I).
 20. The method of claim 19 wherein thepolymerase and the compound are contacted in vitro.
 21. The method ofclaim 19 wherein the polymerase and the compound are contacted in vivo.